Bacteria are evolving immunity to the current generation of antibiotic drugs, raising the need for new drugs and new drug targets. This proposal presents a plan for the structural determination of one such target, the Zn-dependent UDP-3-O-(R-hydroxymyristoyl)-N- acetylglucosamine deacetylase (LpxC) from Aquifex aeolicus. LpxC catalyzes the first committed step in the synthesis of lipid A, the membrane anchor of the principle component of the outer membrane of E. coli and other Gram-negative bacteria. Inhibited lipid A production either kills bacteria or renders them permeable to antibiotics that are normally blocked from entry into the cell. An X-ray crystal structure of LpxC will allow identification of the key features involved in substrate binding and zinc ion coordination, which in turn will aid in the development of new therapeutics that may be bactericidal alone or in conjunction with other known antibiotics.
